The high price of many innovative drugs, which is in part due to costs, time and risks involved in drug development, calls for more efficient approaches to bring drugs to the market. Translational research has been identified as an important component of such strategies. Translational research is not only a function of quality science but also the collaboration of academia and industry, which is best exemplified by success history of bortezomib.
Dipeptide boronate named MG-341 was designed by a straightforward medicinal chemistry approach. Bortezomib was first described in U.S. Pat. No. 5,780,454 with the code MG-341. Because of being proteosome inhibitor, bortezomib is involved in inflammatory responses via activation of NF-kB.
WO 99015183 discloses a method of treatment of inflammatory and autoimmune diseases by administering proteosome inhibitors.
Bortezomib worked very well in animal models of inflammation, especially in rheumatoid arthritis after phase I trial. After phase II trial, multiple myeloma found to be more susceptible to bortezomib based on the study of bortezomib in which bortezomib removed all signs of cancer in a patient of advanced stages of multiple myeloma. Thus, bortezomib was approved by FDA as an injectable small molecule for the treatment of multiple myeloma.
Bortezomib, [(1R)-3-methyl-1-[[(2s)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid, is the first therapeutic anti-neoplastic proteosome inhibitor. Bortezomib is a modified dipeptidyl boronic acid derived from leucine and phenylalanine. Bortezomib works via inhibition of proteolytic activity of proteosome and thus it inhibit degradation of poly-ubiquitinated proteins responsible for catalysis of proteins.
Bortezomib is isolated as trimeric boroxine. Bortezomib as such has poor water solubility, so to overcome this difficulty various dosage forms are formulated.
U.S. Pat. Nos. 6,958,319 and 6,713,446 discloses stable pharmaceutical compositions of boronic acid compounds which are prepared by lyophilization of an aqueous mixture comprising a boronic acid compound and a moiety derived from sugar produces a stable composition that readily releases the boronic acid compound upon dissolution in aqueous media.
U.S. Pat. No. 6,699,835 discloses lyophilized powder form of bortezomib with D-mannitol.
US20110178470 discloses oral and parenteral formulations of bortezomib or its pharmaceutically acceptable salts or solvates, in the form of ready-to-use solution, lyophilized forms or physical admixtures. This patent further discloses processes for preparation of these compositions and methods of using compositions for treating various types of cancers in mammals.
WO2010089768 discloses a bortezomib formulation in which bortezomib is lyophilized with tromethamine.
WO20100114982 discloses lyophilized cake formulation of bortezomib containing bortezomib, cyclodextrin, bulking agent and surfactant.
US20110230441 discloses multi-dose formulation of bortezomib with improved stability, wherein bortezomib is in liquid form suitable for injection with propylene glycol solvent.
US20120083457 discloses lyophilized composition of bortezomib and boric acid in a mass ratio of boric acid to bortezomib is from 1:1 to 10:1.
EP2644189 discloses storage-stable multi-dose liquid formulation of bortezomib with improved stability.
Existed lyophilized products have several disadvantages which includes time consuming reconstitution process, maintenance of dose precision, limited stability in solution form and also lyophilization process for cytotoxic drugs requires exposure of healthcare professional to cytotoxic vapor of the drugs.
To overcome above mentioned problems associated with lyophilized formulation and also to enhance stability and bioavailability of active ingredient, present invention provides ready to dilute injectable pharmaceutical formulations of bortezomib with significantly improved solubility, stability/comparable stability.